DESCRIPTION (Investigator's Abstract): Most strokes are caused by cerebrovascular thrombosis or embolism. Thrombolytic therapy, therefore, should be effective in reducing damage if administered promptly after symptom onset. Unfortunately, there is a risk that some patients will suffer intracerebral hemorrhages when given thrombolytics. Also, stroke is a multifactorial process and it is unlikely that any single form of therapy will be effective in all instances. Preliminary patient trials of thrombolytic agents and some neuroprotective drugs have been encouraging. At present, however, no form of therapy has been proven to be effective for reducing acute stroke damage. Consequently, questions remain concerning the choice of the best thrombolytic agent, how to augment such therapy with neuroprotective drugs, and whether it is possible to reduce serious side effects. Using a coordinated set of animal models, we have already shown that thrombolysis can be both safe and effective, and that neuroprotective agents can ample beneficial therapeutic effects. We also found that the frequency and size of intracerebral hemorrhages are influenced by blood pressure increases that start immediately after the onset of embolic strokes. We propose to study the relative efficacy and safety of some variants of tissue plasminpgen activator (tPA) in our models. These new molecules have improved thrombolytic characteristics compared with natural tPA. We also plan to study the effects of various methods of blood pressure management to determine whether it will be possible to decrease the risks of intracerebral hemorrhaging. We will perform such tests both in the presence and absence of thrombolytic therapy. Finally, we will test the efficacy of several neuroprotective agents in conjunction with thrombolysis. This should help us to identify useful combinations. We anticipate the most effective form of acute stroke therapy will eventually be provided by some form of therapeutic cocktail.